Embryo implantation into the uterine wall is a highly regulated and vital event of early mammalian development. Following hatching from the zona pellucida, the trophectodermal cells surrounding the embryo develop to an attachment competent state. Attachment competent embryos are capable of attaching to and invading a wide variety of cell and tissue types (1-3). The uterus appears to be unique in the sense that it is the only known tissue capable of regulating the invasive potential of the trophoblast. Under most conditions, the uterus is "non-receptive" and will not allow embryos to attach. Conversion to a receptive uterine state is transient and normally coordinated with the development of the embryo by the actions of estrogen and progesterone (4). The task of regulating the uterine receptivity is relegated to the cells lining the uterine lumen, the uterine epithelial cells (UEC). In this regard, a number of morphological studies indicate that the composition of cell surface polysaccharides alters dramatically on both trophectodermal and UEC cell surfaces at the time of embryo attachment. These observations are consistent with an important role for cell surface glycoconjugates in embryo-UEC interactions. Heparan sulfate proteoglycans (HSPGs) are glycoconjugates distributed on cell surfaces and in extracellular matrices of many cell and tissue types (6-8). The constituent polysaccharides of HSPGs appear to participate in or modulate a variety of biological processes including anticoagulation, growth factor binding, regulation of cell proliferation and metabolism and cell adhesion (6-8). With regard to embryo implantation, work in the principal investigator's lab indicates that HSPGs on the embryo cell surface and corresponding HS-binding proteins (HSBPs) of the cell surface of UEC participate in cell adhesion processes occurring in between these cell types in mouse and human model systems. Our hypothesis is that appropriate expression of HS structures and the corresponding HSBPs is critical for trophoblast-UEC interactions. This proposal will employ biochemical, molecular biological and immunochemical approaches to stud), HS-dependent interactions in the initial phase of embryo-UEC binding in vitro and in vivo in mouse and human models. Collectively, these studies will address the molecular basis of embryo-uterine interactions.